Abstracts

Network Theory Identifies a Second Wave of JAK/STAT Signaling in Chronic Epilepsy: Brief Administration of Tofacitinib Provides Long-lasting Protection Against Seizures and Cognitive Comorbidities

Abstract number : 1.008
Submission category : 1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year : 2024
Submission ID : 982
Source : www.aesnet.org
Presentation date : 12/7/2024 12:00:00 AM
Published date :

Authors :
Presenting Author: Olivia Hoffman, BS – University of Wisconsin-Madison

Jennifer Koehler, BA – University of Wisconsin-Madison
Jose Espina, BS, MS – University of Wisconsin-Madison
Anna Patterson, BS – University of Wisconsin-Madison
Emily Gohar, BS – University of Wisconsin-Madison
Emanuel Coleman, BS – Tufts University
Barry Schoenike, BS, MS – University of Wisconsin-Madison
Claudia Espinosa-Garcia, PhD – Emory University
Felipe Paredes, PhD – Emory University
Raymond Dingledine, PhD, Professor – Emory University School of Medicine
Jamie Maguire, PhD, Professor – Tufts University
Avtar Roopra, PhD, Professor – University of Wisconsin-Madison

Rationale: All current drug treatments for epilepsy, a neurological disorder affecting over 50 million people, merely treat symptoms, and a third of patients do not respond to medication. There are no disease modifying treatments that may be administered briefly to epilepsy patients to enduringly eliminate spontaneous seizures and restore cognitive deficits. We previously identified the histone methylase EZH2 as a protective factor and principal regulator of transcriptional changes in rodent dentate granule cells after status epilepticus (SE). We wished to discern the mechanism by which EZH2 induction confers protection in epilepsy in an effort to identify novel therapeutic targets.


Methods: We utilized novel bioinformatic approaches to mine RNAseq profiles of hippocampi from naïve or epileptic EZH2 conditional knockout (EZH2nKO) mice, as well as transcriptomic data from human temporal lobectomies. MAGIC analysis was used to discern the master regulators that drive large scale gene changes in epilepsy across acute and chronic epileptogenesis. Ontological analysis was performed to obtain heuristics describing global gene changes in epilepsy. Predictions were tested in vivo using biochemical and molecular biological techniques to assess gene changes and alterations in protein levels in mouse models of status epilepticus. Flurothyl seizure threshold testing and video-EEG were performed to assess seizure threshold and burden, respectively. Histopathology and evaluation of drug toxicity were assessed by immunofluorescence and immunohistochemistry.


Results: Using bioinformatic network and systems-based approaches on rodent models and human temporal lobectomy samples, we find that induction of the histone methylase EZH2 suppresses epileptogenesis and slows disease progression. Reverse engineering this endogenous protective mechanism highlights a rapid induction of the JAK/STAT3 signaling pathway with status epilepticus (SE), which subsequently undergoes an EZH2-dependent quenching over a period of days. Weeks later, STAT3 reactivates with spontaneous seizures, opening a potent window for intervention in chronic epilepsy. Transient inhibition of the reignited JAK/STAT pathway during chronic epilepsy with the FDA-approved drug CP690550 (Tofacitinib) drives an enduring suppression of seizures and restoration of cognitive decline across preclinical rodent models. CP690550 administration in the chronic period is profoundly disease modifying, with protection lasting at least 2 months after drug withdrawal.


Conclusions: This open discovery approach to characterizing EZH2 function in epilepsy has revealed an endogenous protective response against neuroinflammation, underscored by the pivotal involvement of the JAK/STAT pathway in both the initiation and propagation of epilepsy across preclinical rodent models and human disease. Reignition of JAK/STAT3 inflammatory signaling in chronic epilepsy opens a potent window for enduring seizure suppression and disease modification with the FDA-approved, orally available drug CP690550.


Funding: Supported by CURE (AR), Lily’s Fund (AR), NIH grant 1R01NS108756 (AR, RD) and R01NS105628, R01NS102937, and R21NS120868 (JM).


Basic Mechanisms